Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-γ both induce cardiac hypertrophy in mice
Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-γ both induce cardiac hypertrophy in mice
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DOI：
10.1161/01.res.0000179226.34112.6d
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发表时间：
2005-08-19
影响因子：
20.1
通讯作者：
Mortensen, RM
中科院分区：
文献类型：
--
作者：
Duan, SZ;Ivashchenko, CY;Mortensen, RM
过氧化物酶体增殖物激活受体(PPAR)- γ是脂肪形成所必需的，但也存在于心血管系统中，在心血管系统中，它被认为可以对抗炎症途径并作为生长抑制因子。ppar - γ激动剂，噻唑烷二酮（TZDs），在体外和压力过载模型中抑制心肌细胞生长。矛盾的是，在动物模型中，TZDs也会诱导心脏肥厚。为了直接确定心肌细胞ppar - γ的作用，我们开发了心肌细胞特异性ppar - γ敲除（CM-PGKO）小鼠模型。CM-PGKO小鼠心肌肥厚，心脏收缩功能保留。用TZD（罗格列酮）治疗，在同龄对照小鼠和CM-PGKO小鼠中均诱导心肌肥厚，并激活与CM-PGKO明显不同的肥厚通路。CM-PGKO小鼠发现心脏胚胎基因（心房利钠肽和β -肌球蛋白重链）表达增加，心脏核因子κ B活性升高，罗格列酮治疗没有发现这些作用。罗格列酮增加了不依赖ppar - γ的p38丝裂原活化蛋白激酶的心脏磷酸化，而罗格列酮诱导依赖ppar - γ的心脏细胞外信号相关激酶1/2的磷酸化。罗格列酮或CM-PGKO不影响c-Jun n端激酶的磷酸化。令人惊讶的是，尽管肥大，Akt磷酸化在CM-PGKO小鼠心脏中被抑制。这些数据表明，心肌细胞ppar - γ在体内抑制心脏生长和胚胎基因表达，抑制核因子κ B活性。此外，罗格列酮引起心肌肥大至少部分独立于心肌细胞的ppar - γ，并通过与CM-PGKO不同的机制。
Peroxisome proliferator - activated receptor (PPAR)-gamma is required for adipogenesis but is also found in the cardiovascular system, where it has been proposed to oppose inflammatory pathways and act as a growth suppressor. PPAR-gamma agonists, thiazolidinediones (TZDs), inhibit cardiomyocyte growth in vitro and in pressure overload models. Paradoxically, TZDs also induce cardiac hypertrophy in animal models. To directly determine the role of cardiomyocyte PPAR-gamma, we have developed a cardiomyocyte-specific PPAR-gamma-knockout (CM-PGKO) mouse model. CM-PGKO mice developed cardiac hypertrophy with preserved systolic cardiac function. Treatment with a TZD, rosiglitazone, induced cardiac hypertrophy in both littermate control mice and CM-PGKO mice and activated distinctly different hypertrophic pathways from CM-PGKO. CM-PGKO mice were found to have increased expression of cardiac embryonic genes (atrial natriuretic peptide and beta-myosin heavy chain) and elevated nuclear factor kappa B activity in the heart, effects not found by rosiglitazone treatment. Rosiglitazone increased cardiac phosphorylation of p38 mitogen-activated protein kinase independent of PPAR-gamma, whereas rosiglitazone induced phosphorylation of extracellular signal - related kinase 1/2 in the heart dependent of PPAR-gamma. Phosphorylation of c-Jun N-terminal kinases was not affected by rosiglitazone or CM-PGKO. Surprisingly, despite hypertrophy, Akt phosphorylation was suppressed in CM-PGKO mouse heart. These data show that cardiomyocyte PPAR-gamma suppresses cardiac growth and embryonic gene expression and inhibits nuclear factor kappa B activity in vivo. Further, rosiglitazone causes cardiac hypertrophy at least partially independent of PPAR-gamma in cardiomyocytes and through different mechanisms from CM-PGKO.